TCF7L2 and Wnt Signalling Positively Regulate Leptin Gene Expression in Adipocytes

Abstract

Recent genome-wide association studies (GWAS) have revealed that the Wnt signalling pathway effector TCF7L2 is among the most important diabetes risk genes. Intensive explorations on metabolic function of TCF7L2 in pancreas and liver, however, have generated controversial suggestions. As TCF7L2 is also abundantly expressed in adipocytes, we investigated its expression and function in rodent fat tissue and primary adipocytes. We found that TCF7L2 expression in mouse epididymal fat tissue was physiologically upregulated by feeding, and downregulated in db/db mice and Zucker (fa/fa) rats, 2 obese rodent models. In rat primary adipocytes, 1 nM insulin stimulated TCF7L2 and leptin mRNA expression levels, and the stimulation can be attenuated by iCRT14, an inhibitor of β-catenin-responsive transcription. Insulin at the dosage of 100 nM, however, repressed both TCF7L2 and leptin mRNA levels. The canonical Wnt ligand Wnt3a, but not the non-canonical Wnt ligand Wnt11, was shown to stimulate leptin mRNA expression level and leptin gene promoter activity. Although Wnt3a repressed the differentiation of 3T3-L1 cells toward adipocytes, in either fully differentiated or partially differentiated 3T3-L1 cells, Wnt3a significantly stimulated leptin mRNA levels. Together, our observations suggest that adipocytes TCF7L2 level is metabolic regulated. More importantly, Wnt pathway plays a dual function in adipocytes, including the repression of adipogenesis in pre-adipocytes and the stimulation of leptin production in mature adipocytes, in response to nutritional challenge.